DESCRIPTION: Because of the many similarities between chronic inflammation and the malignant process, and because of the elimination of early neoplastic cells by immune surveillance, there has been a long standing interest in the role of inflammation and innate immunity in cancer. Theses relationships are thought to be particularly relevant to colorectal cancer (CRC) because of its well-established strong associations with history of inflammatory bowel disease and use of non-steroidal anti-inflammatory drug, and the presence in the gut of a remarkably abundant immune system that is constantly stimulated by commensal bacteria. The proposed study will use existing data and specimens from the Colon Cancer Family Registry (CCFR) and the Multiethnic Cohort (MEC) to test the hypothesis that inherited variants in key genes in the inflammation and innate immunity pathways result in a pro-inflammatory predisposition and weak cytotoxic defense that confer an increased risk of CRC. We propose in Aim 1 to conduct a case-control study using the White discordant sibpairs participating in the Colon CFR (2,488 CRC cases, 4,280 controls) to test the association of CRC with ~700 tagSNPs in genes in these pathways. The 38 genes selected were prioritized based on biological relevance and functional evidence. For each locus, tagSNPs will be selected using linkage disequilibrium (R2>0.9, MAF>0.05) from a dense SNP map constructed primarily from HapMap. In Aim 2, we will test approximately 10% of the most strongly associated SNPs in Aim 1, as well as additional tagSNPs at these loci and AIMs, in a second case-control study (2,768 CRC cases and 2,768 controls) nested in the MEC, in order to validate the findings and investigate heterogeneity of effects across ethnic/racial groups. The family-based design will fully protect Aim 1 against population stratification. Aim 2 will take advantage of the genetic and lifestyle heterogeneity of MEC participants and of the prospective nature of their exposure data to control Type I error, assess effect heterogeneity across ethnic/racial populations, and investigate GxG and GxE interactions. The association of inherited variants in inflammation or innate immunity-related genes with CRC would corroborate the etiologic role of persistent, sub-clinical inflammation in this cancer. It may also provide a means to identify susceptible sub-groups which may particularly benefit from NSAIDs chemoprevention and screening. PUBLIC HEALTH RELEVANCE: The proposed study will test the association of inherited variants in inflammation and innate immunity-related genes with colorectal cancer in order to confirm the causative role of persistent, sub-clinical inflammation for this cancer. It may also provide a means to identify susceptible sub-groups which may particularly benefit from intensive screening and/or primary prevention with non-steroidal inflammatory drugs.